Abstract

Background

Transcranial Direct Current Stimulation (tDCS) is an emerging approach for improving capacity in activities of daily living (ADL) and upper limb function after stroke. However, it remains unclear what type of tDCS stimulation is most effective. Our aim was to give an overview of the evidence network regarding the efficacy and safety of tDCS and to estimate the effectiveness of the different stimulation types.

Methods

We performed a systematic review of randomised trials using network meta-analysis (NMA), searching the following databases until 5 July 2016: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, and four other databases. We included studies with adult people with stroke. We compared any kind of active tDCS (anodal, cathodal, or dual, that is applying anodal and cathodal tDCS concurrently) regarding improvement of our primary outcome of ADL capacity, versus control, after stroke. PROSPERO ID: CRD42016042055.

Results

We included 26 studies with 754 participants. Our NMA showed evidence of an effect of cathodal tDCS in improving our primary outcome, that of ADL capacity (standardized mean difference, SMD = 0.42; 95% CI 0.14 to 0.70). tDCS did not improve our secondary outcome, that of arm function, measured by the Fugl-Meyer upper extremity assessment (FM-UE). There was no difference in safety between tDCS and its control interventions, measured by the number of dropouts and adverse events.

Conclusion

Comparing different forms of tDCS shows that cathodal tDCS is the most promising treatment option to improve ADL capacity in people with stroke.

tDCS is relatively inexpensive, easy to administer and portable, hence constituting an ideal adjuvant therapy during stroke rehabilitation. It works by applying a weak and constant direct current to the brain and has the ability to either enhance or suppress cortical excitability, with effect lasting up to several hours after the stimulation [7, 8, 9]. Hypothetically, this technique makes tDCS a potentially useful tool to modulate neuronal inhibitory and excitatory networks of the affected and the non-affected hemisphere post stroke to enhance, for example, upper limb motor recovery [10, 11]. Three different stimulation types can be distinguished.

In anodal stimulation, the anodal electrode (+) usually is placed over the lesioned brain area and the reference electrode over the contralateral orbit [12]. This leads to subthreshold depolarization, hence promoting neural excitation [3].

In cathodal stimulation, the cathode (−) usually is placed over the non-lesioned brain area and the reference electrode over the contralateral orbit [12], leading to subthreshold polarization and hence inhibiting neural activity [3].

However, the literature does not provide clear guidelines, not only regarding the tDCS type, but also regarding the electrode configuration [14], the amount of current applied and the duration of tDCS, or the question if tDCS should be applied as a standalone therapy or in combination with other treatments, like robot-assisted therapy [15].

Rationale

There is so far conflicting evidence from systematic reviews of randomised controlled trials on the effectiveness of different tDCS approaches after stroke. For example, over the past two decades more than 30 randomised clinical trials have investigated the effects of different tDCS stimulation techniques for stroke, and there are 55 ongoing trials [16]. However, the resulting network of evidence from randomised controlled trials (RCTs) investigating different types of tDCS (i.e., anodal, cathodal or dual) as well as their comparators like sham tDCS, physical rehabilitation or pharmacological agents has not yet been analyzed in a systematic review so far.

A network meta-analysis (NMA), also known as multiple treatment comparison meta-analysis or mixed treatment comparison analysis, allows for a quantitative synthesis of the evidence network. This is made possible by combining direct evidence from head-to-head comparisons of three or more interventions within randomised trials with indirect evidence across randomised trials on the basis of a common comparator [17, 18, 19, 20]. Network meta-analysis has many advantages over traditional pairwise meta-analysis, such as visualizing and facilitating the interpretation of the wider picture of the evidence and improving understanding of the relative merits of these different types of neuromodulation when compared to sham tDCS and/or another comparator such as exercise therapy and/or pharmacological agents [21, 22]. By borrowing strength from indirect evidence to gain certainty about all treatment comparisons, network meta-analysis allows comparative effects that have not been investigated directly in randomised clinical trials to be estimated and ranked [22, 23].

Objective

The aim of our systematic review with NMA was to give an overview of the evidence network of randomised controlled trials of tDCS (anodal, cathodal, or dual) for improving capacity in activities of daily living (ADL) and upper limb function after stroke, as well as its safety, and to estimate and rank the relative effectiveness of the different stimulation types, while taking into account potentially important treatment effect modifiers.

Abstract

Background

Recovery of handgrip is critical after stroke since it is positively related to upper limb function. To boost motor recovery, transcranial direct current stimulation (tDCS) is a promising, non-invasive brain stimulation technique for the rehabilitation of persons with stroke. When applied over the primary motor cortex (M1), tDCS has been shown to modulate neural processes involved in motor learning. However, no studies have looked at the impact of tDCS on the learning of a grip task in both stroke and healthy individuals.

Objective

To assess the use of tDCS over multiple days to promote motor learning of a grip task using a learning paradigm involving a speed-accuracy tradeoff in healthy individuals.

Methods

In a double-blinded experiment, 30 right-handed subjects (mean age: 22.1 ± 3.3 years) participated in the study and were randomly assigned to an anodal (n = 15) or sham (n = 15) stimulation group. First, subjects performed the grip task with their dominant hand while following the pace of a metronome. Afterwards, subjects trained on the task, at their own pace, over 5 consecutive days while receiving sham or anodal tDCS over M1. After training, subjects performed de novo the metronome-assisted task. The change in performance between the pre and post metronome-assisted task was used to assess the impact of the grip task and tDCS on learning.

Conclusions

Anodal tDCS is effective in promoting grip motor learning in healthy individuals. Further studies are warranted to test its potential use for the rehabilitation of fine motor skills in stroke patients.

Results

There was no significant effect of tDCS on PASSMA→M1 induced plasticity in the repeated-measures ANOVA. However, post-hoc within-subject contrasts revealed a significant tDCS with PASSMA→M1 interaction. This was explained by PA-tDCS and AP-tDCS modifying the PASSMA→M1 effect into the same direction in 13/15 subjects (87%, p = 0.004 for deviation from equality). Sizes of the PA-tDCS and AP-tDCS effects were correlated (rs = 0.53, p = 0.044). A control experiment demonstrated that PA-tDCS and AP-tDCS alone (without PASSMA→M1) had no effect on MEP amplitude.

Conclusions

Data point to unidirectional tDCS effects on PASSMA→M1 induced plasticity irrespective of tDCS polarity, in contrast to our hypothesis. We propose that radial symmetry of cortical columns, gyral geometry of motor cortex, and cooperativity of plasticity induction can explain the findings.

Highlights

– Clinical and research interest in noninvasive brain stimulation has grown exponentially.– Here, we present the main findings on the physiological basis of transcranial electric stimulation (tES).– In a second part, we discuss evidence for applications of tES in behavioral research and clinical settings.– We note several challenges which need to be addressed before extensive clinical use of tES.

Abstract

Non-invasive brain stimulation (NIBS) has been gaining increased popularity in human neuroscience research during the last years. Among the emerging NIBS tools is transcranial electrical stimulation (tES), whose main modalities are transcranial direct, and alternating current stimulation (tDCS, tACS). In tES, a small current (usually less than 3 mA) is delivered through the scalp. Depending on its shape, density, and duration, the applied current induces acute or long-lasting effects on excitability and activity of cerebral regions, and brain networks. tES is increasingly applied in different domains to (a) explore human brain physiology with regard to plasticity, and brain oscillations, (b) explore the impact of brain physiology on cognitive processes, and (c) treat clinical symptoms in neurological and psychiatric diseases. In this review, we give a broad overview of the main mechanisms and applications of these brain stimulation tools.

Abstract

Objective

Design

Double-blind randomized controlled trial with placebo control.

Setting

An outpatient department of a local medical center.

Participants

People (n = 25) with chronic stroke were randomly assigned to 2 groups. Participants in the transcranial direct current stimulation with sensory modulation (tDCS-SM) and in the control group were 55.3±11.5 (n=14) and 56.9±13.5 (n=11) years old, respectively.

Interventions

8-week intervention. The tDCS-SM group received bilateral tDCS, bilateral cutaneous anesthesia, and high repetitions of passive movements on the paretic hand. The control group received the same passive movements but with sham tDCS and sham anesthesia. During the experiment, all participants continued their regular rehabilitation.

Main outcome measures

Voluntary UE movement, spasticity, UE function, and basic activities of daily living. Outcomes were assessed at baseline, at post-intervention, and at 3- and 6-month follow-ups.

Results

No significant differences were found between groups. However, there was a trend that the voluntary UE movement improved more in the tDCS-SM group than in the control group, with a moderate immediate effect (partial η2, ηp2 = 0.14, p = 0.07) and moderate long-term effects (ηp2 =0.17, p = 0.05 and ηp2 = 0.12, p = 0.10). Compared with the control group, the tDCS-SM group had a trend of a small immediate effect (ηp2 = 0.02 – 0.04) on reducing spasticity but no long-term effect. A trend of small immediate and long-term effects in favor of tDCS-SM was found on UE function and daily function recovery (ηp2= 0.02 – 0.09).

Conclusions

Accompanied with traditional rehabilitation, tDCS-SM had a non-significant trend of having immediate and longitudinal effects on voluntary UE movement recovery in patients with severe to moderate UE paresis after stroke, but its effects on spasticity reduction and functional recovery may be limited. (NCT01847157)

Objectives: Transcranial direct current stimulation (tDCS) is one type of neuromodulation, which is an emerging technology that holds promise for the future studies on therapeutic and diagnosis applications in treatment of neurological and psychiatric diseases. However, there is a serious question among developing countries with limited financial and human resources, about the potential returns of an investment in this field and regarding the best time to transfer this technology from controlled experimental settings to health systems in the public and private sectors. This article reviews the tDCS as tools of neuromodulation for stroke and discusses the opportunities and challenges available for clinicians and researchers interested in advancing neuromodulation therapy. The aim of this review is to highlight the usefulness of tDCS and to generate an interest that will lead to appropriate studies that assess the true clinical value of tDCS for brain diseases in developing countries.

Methods: Literature review was done on PubMed from 2016 on neuromodulation in under-developed countries (UDCs) by non-invasive brain stimulation methods, using the key words “stroke”, “rehabilitation”, and “tDCS”.

Results: We first identified articles and websites, of which were further selected for extensive analysis mainly based on clinical relevance, study quality and reliability, and date of publication.

Conclusion: Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity to use in mostly UDCs.

INTRODUCTION
During stroke, an interruption to all or part of the brain’s
blood supply, with the subsequent deprivation of oxygen
and glucose to the affected area, causes the rapid loss
of brain function through the destruction of neuronal
function and the initiation of an ischemic cascade that
seriously damages or kills neurons1. Strokes are
classified as an ischemic (caused by embolism,
thrombosis or systemic hypoperfusion) approximately
80% and hemorrhagic (intracerebral, subarachnoid,
subdural or epidural in type) strokes(1, 2). The main
symptoms associated with stroke are weakness in
facial, speech and a loss in visual field and paralysis in
the arm or leg. These symptoms may last only a few
hours and disappear completely within 24 hours, as
with TIAs, but even under these circumstances,
immediate medical assistance should be sought, as
this will help minimise damage to the brain and help
prevent progression to larger, more serious episodes of
stroke(2). Stroke can result in lasting neurological
damage or may even cause death unless it is
diagnosed and treated promptly. When the stroke is
severe, the patient often faces a prolonged stay in
hospital and, following their discharge and depending
on the severity of the consequences, constant care.
This care is either provided by a family member or, in
the most severe cases, by a nursing home. Stroke
disease not only affects health-related quality of life
(HRQOL) of patients but it can also increase their
hospital length of stay (HLoS)(3, 4). HLoS will even be
more increased if patients are suffering with stroke
combined with diabetes mellitus and hypertension(5). […]

OBJECTIVE. To determine the impact of transcranial direct current stimulation (tDCS) combined with repetitive, task-specific training (RTP) on upper-extremity (UE) impairment in a chronic stroke survivor with moderate impairment.

METHOD. The participant was a 54-yr-old woman with chronic, moderate UE hemiparesis after a single stroke that had occurred 10 yr before study enrollment. She participated in 45-min RTP sessions 3 days/wk for 8 wk. tDCS was administered concurrent to the first 20 min of each RTP session.

RESULTS. Immediately after intervention, the participant demonstrated marked score increases on the UE section of the Fugl–Meyer Scale and the Motor Activity Log (on both the Amount of Use and the Quality of Movement subscales).

CONCLUSION. These data support the use of tDCS combined with RTP to decrease impairment and increase UE use in chronic stroke patients with moderate impairment. This finding is crucial, given the paucity of efficacious treatment approaches in this impairment level.

Abstract

This narrative review aims to provide an objective view of the non-invasive neuromodulation (NINM) protocols available for treating spasticity, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). On the basis of the relevant randomized controlled trials, we infer that NINM is more effective in reducing spasticity when combined with the conventional therapies than used as a stand-alone treatment. However, the magnitude of NINM aftereffects depends significantly on the applied hemisphere and the underlying pathology. Being in line with these arguments, low-frequency rTMS and cathodal-tDCS over the unaffected hemisphere are more effective in reducing spasticity than high-frequency rTMS and anodal-tDCS over the affected hemisphere in chronic post-stroke. However, most of the studies are heterogeneous in the stimulation setup, patient selection, follow-up duration, and the availability of the sham operation. Therefore, the available data on the usefulness of NINM in reducing spasticity need to be confirmed by further larger and multicentric randomized controlled trials to gather evidence on the efficiency of NINM regimens in reducing spasticity in various neurologic conditions.

Abstract

Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two types of non-invasive transcranial brain stimulation (TBS). They are useful tools for stroke research and may be potential adjunct therapies for functional recovery. However, stroke often causes large cerebral lesions, which are commonly accompanied by a secondary enlargement of the ventricles and atrophy. These structural alterations substantially change the conductivity distribution inside the head, which may have potentially important consequences for both brain stimulation methods. We therefore aimed to characterize the impact of these changes on the spatial distribution of the electric field generated by both TBS methods. In addition to confirming the safety of TBS in the presence of large stroke-related structural changes, our aim was to clarify whether targeted stimulation is still possible. Realistic head models containing large cortical and subcortical stroke lesions in the right parietal cortex were created using MR images of two patients. For TMS, the electric field of a double coil was simulated using the finite-element method. Systematic variations of the coil position relative to the lesion were tested. For TDCS, the finite-element method was used to simulate a standard approach with two electrode pads, and the position of one electrode was systematically varied. For both TMS and TDCS, the lesion caused electric field “hot spots” in the cortex. However, these maxima were not substantially stronger than those seen in a healthy control. The electric field pattern induced by TMS was not substantially changed by the lesions. However, the average field strength generated by TDCS was substantially decreased. This effect occurred for both head models and even when both electrodes were distant to the lesion, caused by increased current shunting through the lesion and enlarged ventricles. Judging from the similar peak field strengths compared to the healthy control, both TBS methods are safe in patients with large brain lesions (in practice, however, additional factors such as potentially lowered thresholds for seizure-induction have to be considered). Focused stimulation by TMS seems to be possible, but standard tDCS protocols appear to be less efficient than they are in healthy subjects, strongly suggesting that tDCS studies in this population might benefit from individualized treatment planning based on realistic field calculations.

1. Introduction

Transcranial brain stimulation (TBS) methods are useful tools to induce and to quantify neural plasticity, and as such are increasingly being used in stroke research and as potential adjunct therapies in stroke rehabilitation. The cerebral lesions caused by stroke result in persisting physical or cognitive impairments in around 50% of all survivors (Di Carlo, 2008; Leys et al., 2005 ; Young and Forster, 2007), meaning that new therapies are urgently needed. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two TBS approaches which are being increasingly utilised in stroke research. Single-pulse TMS combined with electromyography (EMG) or electroencephalography (EEG) can be used to assess cortical excitability, for example to index the functional state of the perilesional tissue. The neuromodulatory effects of repetitive TMS protocols (rTMS) may, in association with neuro-rehabilitative treatments, enhance motor recovery (Liew et al., 2014). Similar results have been demonstrated for TDCS. For example, anodal TDCS of the hand area in the primary motor cortex has been shown to improve motor performance of the affected hand (Allman et al., 2016; Hummel et al., 2005 ; Stagg et al., 2012) and anodal TDCS applied over the left frontal cortex enhanced naming accuracy in patients with aphasia (Baker et al., 2010). However, not all studies report a clear-cut positive impact of TBS on the stroke symptoms. Rather, the observed effects are often weak and not consistent across patients, demonstrating the need for a better understanding of the underlying biophysical and physiological mechanisms.

Compared with healthy subjects, several factors might contribute to a change in the neuroplastic response to TBS protocols in stroke patients, including changes in the neural responsiveness to the applied electric fields, as well as differences in the underlying physiology and metabolism (Blicher et al., 2009; Blicher et al., 2015 ; O’Shea et al., 2014). When the lesions are large, they may also substantially alter the generated electric field pattern, meaning that the assumptions on spatial targeting as derived from biophysical modelling and physiological experiments in healthy subjects might no longer be valid. Stroke lesions are often accompanied by secondary macrostructural changes such as cortical atrophy and enlargement of the ventricles (e.g., Skriver et al., 1990), which may further contribute to changes in the field pattern. In addition, the safety of TBS in patients with large lesions needs to be further clarified, as it is possible that the lesions might cause stimulation “hot spots”. In chronic patients, the stroke cavity becomes filled with corticospinal fluid (CSF), which might cause shunting of current, funnelling the generated currents towards the surrounding brain tissue and potentially causing localized areas of dangerously high field strengths.

Here, using finite-element calculations and individual head models derived from structural MR images, we focused on the impact of a large cortical lesion in chronic stroke on the electric field pattern generated in the brain by TMS and TDCS, respectively. Firstly, we assessed the safety of the stimulation by comparing the achieved field strengths with those estimated for a healthy control. Secondly, we tested how reliably we can accurately target the perilesional tissue, often the desired target for TBS, as reorganisation here is thought to underpin functional recovery (Kwakkel et al., 2004). Finally, we were also interested to see whether any observed changes in the field pattern were specific to a patient with a cortical lesion (which is connected to the CSF layer underneath the skull), or whether similar effects might occur in case of large chronic subcortical lesion. We therefore additionally tested the field distribution in a head model of a patient with a subcortical lesion occurring at a similar position as the cortical lesion.

2. Materials and methods

2.1. Selection of patients

The aim of this study was to characterize the effect of a large chronic cortical stroke lesion on the electric field distribution generated by TBS, and to compare the effects of this lesion to that caused by a large chronic subcortical lesion. MR images of several patients were visually inspected to select two datasets, which had a cortical [P01] and subcortical lesion [P02], respectively, within the same gross anatomical regions.

Patient P01 was a 36 year old female with episodic migraine; she was admitted with left hemiparalysis, fascial palsy and a total NIHSS score of 16 due to a right ICI/MCI occlusion. She was treated with IV thrombolysis and thrombectomy and recanalization was achieved 5 h after symptom onset. One year post-stroke she still suffered from motor impairment (Wolf Motor Function Test [WMFT] score of 30) and was scanned as part of a clinical study investigating the effect of combining Constraint-Induced Movement Therapy and tDCS (Figlewski et al., 2017; Clinical trials NCT01983319, Regional Ethics approval: 1-10-72-268-13). The structural scans showed a cortical lesion in the right parietal lobe (Fig. 1A). The lesion volume, delineated manually with reference to T1- and T2-weighted imaging, was 26,415 mm3.

Fig. 1.

A) Coronal view of patient P01 with a cortical lesion in the right hemisphere. The top shows the T1-weighted MR image and the bottom the reconstructed head mesh. The view was chosen to include the lesion centre. The lesion is marked by red dashed circles. B) Corresponding view of patient P02 with a large subcortical lesion at a similar location in the right hemisphere. C) Corresponding view of the data set of the healthy control. D) The coil and electrode positions were systematically moved along two directions that were approximately perpendicular to each other. Five positions were manually placed every 2 cm in posterior – anterior direction symmetrically around the centre of the cortical lesion. The same was repeated along the lateral – medial direction. Both lines share the same centre position above the lesion, resulting in 9 positions in total. E) At each position, two coil orientations were tested which resulted in a current flow underneath the coil centre from anterior to posterior (top) and from lateral to medial, respectively (bottom). F) For each position of the yellow “stimulating” electrode, two positions of the blue return electrode were tested. First, the contralateral equivalent of the electrode position above the centre of the cortical lesion was used (top). In addition, a position on the contralateral forehead was tested (bottom).

Patient P02 was a 44 year old female. She woke up with a left hemiparesis and an acute CT scan showed no bleeding. No IV thrombolysis was given due to uncertain timing of symptom onset. An embolic stroke was suspect due to a patent foramen ovale, which was subsequently closed. She was scanned with MRI 9 months post stroke showing a right subcortical infarct, at which time she had a WMFT score of 8. The lesion volume, delineated as for P01, was 56,010 mm3. She was scanned as part of a clinical study investigating the effect of combining tDCS with daily motor training (Allman et al., 2016; Regional Ethics approval: Oxfordshire REC A; 10/H0604/98)….

The present study investigated the effects of anodal transcranial direct current stimulation (tDCS) on lower extremity muscle strength training in 24 healthy participants. In this triple-blind, sham-controlled study, participants were randomly allocated to the anodal tDCS plus muscle strength training (anodal tDCS) group or sham tDCS plus muscle strength training (sham tDCS) group. Anodal tDCS (2 mA) was applied to the primary motor cortex of the lower extremity during muscle strength training of the knee extensors and flexors. Training was conducted once every 3 days for 3 weeks (7 sessions). Knee extensor and flexor peak torques were evaluated before and after the 3 weeks of training. After the 3-week intervention, peak torques of knee extension and flexion changed from 155.9 to 191.1 Nm and from 81.5 to 93.1 Nm in the anodal tDCS group. Peak torques changed from 164.1 to 194.8 Nm on extension and from 78.0 to 85.6 Nm on flexion in the sham tDCS group. In both groups, peak torques of knee extension and flexion significantly increased after the intervention, with no significant difference between the anodal tDCS and sham tDCS groups. In conclusion, although the administration of eccentric training increased knee extensor and flexor peak torques, anodal tDCS did not enhance the effects of lower extremity muscle strength training in healthy individuals. The present null results have crucial implications for selecting optimal stimulation parameters for clinical trials.

Lower leg muscle strength is an important motor function required for patients who have had a stroke to regain activities of daily living (ADL). Lower leg muscle strength correlates with performance in activities, including sit-to-stand, gait, and stair ascent (Bohannon, 2007). Furthermore, lower leg muscle strength training increases muscle strength and improves ADL in patients with stroke (Ada et al., 2006). Therefore, lower leg muscle strength training is one of the important activities rehabilitating patients with stroke to regain their independence in ADL.

Several studies have examined the effect of a single session of tDCS on lower leg muscle strength, although the evidence is inconsistent (Tanaka et al., 2009, 2011; Montenegro et al., 2015, 2016; Angius et al., 2016; Washabaugh et al., 2016). Its effects seem dependent on tDCS protocols, training tasks, muscle groups, and subject populations. Although, most tDCS studies on lower leg muscle strength have focused on the acute effects of a single tDCS application, to the best of our knowledge, no study has examined how lower extremity strength training combined with repeated sessions of tDCS affects lower leg muscle strength. This type of investigation has strong clinical implications for the application of tDCS in rehabilitation for patients with lower leg muscle weakness.